Dioxolenone bromides of the structure ##STR2## where Z is phenyl, methyl, t-butyl, or hydrogen, have been prepared by the bromination of dioxolenone starting materials of the structure ##STR3##
U.S. applications Ser. Nos. 266,888 and 266,843 (U.S. Pat. No. 5,470,845) each filed Jul. 5, 1994 (files Nos. HX59b and HX59c) disclose phosphonosulfonate squalene synthetase inhibitors of the structure ##STR4## wherein R.sup.2 is OR.sup.5 or R.sup.5a,
R.sup.3 and R.sup.5 are independently H, alkyl, arylalkyl, aryl, cycloalkyl, metal ion or other pharmaceutically acceptable salt, or prodrug ester; PA1 R.sup.5a is H, alkyl, arylalkyl or aryl; PA1 R.sup.4 is H, alkyl, aryl, cycloalkyl, arylalkyl, metal ion, or other pharmaceutically acceptable salt, or prodrug ester; PA1 R.sup.1 is a lipophilic group containing at least 7 carbons; PA1 Z is H, halogen, lower alkyl or lower alkenyl. PA1 (1-alkanoyloxy)alkyl such as, ##STR6## wherein R.sup.18, R.sup.19 and R.sup.20 are H, alkyl, aryl or aryl-alkyl; however R.sup.18 O cannot be HO. Examples of such prodrug esters include ##STR7## Other examples of prodrug esters disclosed include ##STR8## wherein R.sup.18 can be H, alkyl (such as methyl or t-butyl), arylalkyl (such as benzyl) or aryl (such as phenyl); R.sup.21 is H, alkyl, halogen or alkoxy, R.sup.22 is alkyl, aryl, arylalkyl or alkoxyl, and n.sub.1 is 0, 1 or 2; or R.sup.3 and R.sup.5 can be linked together as in ##STR9## PA1 R.sup.3 and R.sup.5 are independently H, alkyl, arylalkyl, aryl, cycloalkyl, metal ion or other pharmaceutically acceptable cation or salt; PA1 R.sup.5a is alkyl, arylalkyl or aryl; PA1 R.sup.4 is H, metal ion, or other pharmaceutically acceptable cation or salt; PA1 R.sup.1 is a lipophilic group containing at least 7 carbons such as Ar.sup.1 --O--Ar.sup.2 wherein Ar.sup.1 is an aryl group, Ar.sup.2 is an aryl group and p is 1 to 15; and PA1 Z is H, halogen, lower alkyl or lower alkenyl. PA1 R.sub.2 is alkyl or arylalkyl, preferably benzyl, para-methoxybenzyl or diphenylmethyl, as well as para-nitrobenzyl, ortho-nitrobenzyl or triphenylmethyl; and PA1 R.sup.x is alkyl of at least 2 carbons, preferably of at least 3 carbons, such as n-propyl, i-propyl, n-butyl and t-butyl. PA1 R.sup.3 and R.sup.5 are independently H, alkyl, arylalkyl, aryl or cycloalkyl; PA1 R.sup.5a is H, alkyl, arylalkyl or aryl; PA1 R.sup.4 is H, alkyl, aryl, cycloalkyl or arylalkyl; PA1 R.sup.1 is a lipophilic group containing at least 7 carbons; PA1 Z is H, halogen, lower alkyl or lower alkenyl; PA1 is treated with an amine base such as diisopropylethylamine, triethylamine, N-methylmorpholine or tributylamine, preferably diisopropylethylamine, in the presence of an inert organic solvent such as acetonitrile, N,N'-dimethyl-formamide and methylene chloride, and the so-formed solution is treated with dioxolenone bromide VI of the structure VI ##STR26## where R is alkyl or aryl, to form the ester of the structure XI ##STR27## (XI and XIA are novel compounds) wherein R.sup.1 is a lipophilic group and M is a metal ion as defined herein such as Na, Li or K, or NH.sub.4.sup.+.
The R.sup.1 group is alkyl containing 7 to 25 carbons in the chain; alkenyl containing from 7 to 25 carbon atoms in the chain and from 1 to 6 double bonds; alkynyl containing 1 to 6 triple bonds; mixed alkenyl-alkynyl containing 1 to 5 double bonds and 1 to 5 triple bonds; or aryl; and where in the above groups alkenyl, alkynyl and/or aryl may be substituted or unsubstituted; cycloheteroalkyl linked through a carbon on the ring or a heteroatom; cycloalkyl; heteroarylalkyl; cycloalkylalkyl; heteroaryl; cycloheteroalkylalkyl; or a group of the structure ##STR5## wherein Ar is aryl or heteroaryl, and Ar may include one to three additional rings fused to Ar, and wherein (CH.sub.2).sub.p contains from 1 to 15 carbons in the chain and may include 0, 1, 2 or 3 double bonds and/or 0, 1, 2 or 3 triple bonds in the normal chain, and may contain an ether or amino function in the chain, and/or may include 0, 1, 2 or 3 substituents as defined below for R.sup.6 ; and R.sup.6, R.sup.7, R.sup.8 and R.sup.8a are the same or different and are H, alkyl containing 1 to 40 carbons, alkoxy containing 1 to 40 carbons, alkenyl containing 2 to 40 carbons, alkenyloxy containing 2 to 40 carbons, alkynyl containing 2 to 40 carbons, alkynyloxy containing 2 to 40 carbons, hydroxy, halogen, nitro, amino, thiol, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl, cycloalkyl, cycloalkylalkyl, Ar-alkyl, ArO, Ar-amino, Ar, Ar-thio, Ar-sulfinyl, Ar-sulfonyl, cyano, Ar-carbonyloxy, or Ar-carbonylamino.
The above applications disclose prodrug esters for the above compounds which are known in the art for both phosphorus and carboxylic acids. Examples of prodrug esters disclosed include the following:
U.S. application Ser. No. 295,121 filed Aug. 24, 1994, U.S. Pat. No. 5,447,922, discloses .alpha.-phosphonosulfinate squalene synthetase inhibitors having the structure ##STR10## wherein R.sup.2 is OR.sup.5 or R.sup.5a,